Description: (Applicant's Description) Prospective studies of 60,984 men in Haimen City, China and 19,469 men in Senegal, west Africa revealed a 14-fold greater death rate from hepatocellular carcinoma (HCC) among the Haimen (168 per 100,000) than the Senegalese cohort (12 per 100,000). Even though chronic infection with hepatitis B virus (HBV) is the major risk factor for HCC in both populations, the age-adjusted prevalence of chronic infection is about 20% in both cohorts. Exposure to aflatoxin, a postulated major risk factor for HCC, is also similar or greater in the Senegalese population. The prevalence of viremia (HBV DNA in serum) among HBV carriers throughout adult life, however, is much higher among the Chinese than the Senegalese population. Nevertheless, within the Chinese cohort, viremia at study entry is not a risk factor for HCC after four years of follow-up. The aims of this project focus on factors that may account for variation in HCC risk in the Chinese and Senegalese cohorts and a cohort of Asian-American HBV carriers living in the Philadelphia area. Continued tracking of these three cohorts will test the hypothesis that with longer duration of follow-up, H B V v iremia and liver damage at study entry are associated with person-specific risks of HCC and that aflatoxin-B1 (AFB1)-albumin adducts are a s s ociated with development of HCC among viremic individuals and/or genotypically determined poor detoxifiers of AFB1 (in collaboration with Project 2). In close cooperation with the studies of WHV in woodchucks (Project 3), an intensive longitudinal study of 1000 male and female HBV carriers in these three populations will be conducted to: a) examine whether perturbations of the stability of HBV serum markers are associated with acute illnesses, aflatoxin exposure, and/or outgrowth of viral mutants; b) assay hepatocyte turnover and immune responses in liver biopsies; c) correlate these measures with viral load; d) examine the relationship of sex differences in changes in HBV serum markers over time to the lower HCC risk of female HBV carriers. Because present studies show that an episode of acute hepatitis in adulthood approximately doubles HCC risk among both HBV carriers and non-carriers, the causes and outcomes of 200 cases of acute hepatitis in Haimen City will be characterized. This research will lead to a new level of understanding of the factors that lead to HCC and to new strategies for the prevention of this lethal disease.